α-Ketoglutarate Inhibits Thrombosis and Inflammation by Prolyl Hydroxylase-2 Mediated Inactivation of Phospho-Akt

Background: Phospho-Akt1 (pAkt1) undergoes prolyl hydroxylation at Pro125 and Pro313 by the prolyl hydroxylase-2 (PHD2) in a reaction decarboxylating α-ketoglutarate (αKG). We investigated whether the αKG supplementation could inhibit Akt-mediated activation of platelets and monocytes, in vitro as w...

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Autores principales:	Nishith M Shrimali, Sakshi Agarwal, Simrandeep Kaur, Sulagna Bhattacharya, Sankar Bhattacharyya, Josef T Prchal, Prasenjit Guchhait
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	αKG PHD2 Akt thrombosis inflammation SARS-CoV-2 Medicine R Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/1f095c1e831047149bf72cc927d00585
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spelling	oai:doaj.org-article:1f095c1e831047149bf72cc927d005852021-11-04T04:32:41Zα-Ketoglutarate Inhibits Thrombosis and Inflammation by Prolyl Hydroxylase-2 Mediated Inactivation of Phospho-Akt2352-396410.1016/j.ebiom.2021.103672https://doaj.org/article/1f095c1e831047149bf72cc927d005852021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352396421004667https://doaj.org/toc/2352-3964Background: Phospho-Akt1 (pAkt1) undergoes prolyl hydroxylation at Pro125 and Pro313 by the prolyl hydroxylase-2 (PHD2) in a reaction decarboxylating α-ketoglutarate (αKG). We investigated whether the αKG supplementation could inhibit Akt-mediated activation of platelets and monocytes, in vitro as well as in vivo, by augmenting PHD2 activity. Methods: We treated platelets or monocytes isolated from healthy individuals with αKG in presence of agonists in vitro and assessed the signalling molecules including pAkt1. We supplemented mice with dietary αKG and estimated the functional responses of platelets and monocytes ex vivo. Further, we investigated the impact of dietary αKG on inflammation and thrombosis in lungs of mice either treated with thrombosis-inducing agent carrageenan or infected with SARS-CoV-2. Findings: Octyl αKG supplementation to platelets promoted PHD2 activity through elevated intracellular αKG to succinate ratio, and reduced aggregation in vitro by suppressing pAkt1(Thr308). Augmented PHD2 activity was confirmed by increased hydroxylated-proline and enhanced binding of PHD2 to pAkt in αKG-treated platelets. Contrastingly, inhibitors of PHD2 significantly increased pAkt1 in platelets. Octyl-αKG followed similar mechanism in monocytes to inhibit cytokine secretion in vitro. Our data also describe a suppressed pAkt1 and reduced activation of platelets and leukocytes ex vivo from mice supplemented with dietary αKG, unaccompanied by alteration in their number. Dietary αKG significantly reduced clot formation and leukocyte accumulation in various organs including lungs of mice treated with thrombosis-inducing agent carrageenan. Importantly, in SARS-CoV-2 infected hamsters, we observed a significant rescue effect of dietary αKG on inflamed lungs with significantly reduced leukocyte accumulation, clot formation and viral load alongside down-modulation of pAkt in the lung of the infected animals. Interpretation: Our study suggests that dietary αKG supplementation prevents Akt-driven maladies such as thrombosis and inflammation and rescues pathology of COVID19-infected lungs. Funding: Study was funded by the Department of Biotechnology (DBT), Govt. of India (grants: BT/PR22881 and BT/PR22985); and the Science and Engineering Research Board, Govt. of India (CRG/000092).Nishith M ShrimaliSakshi AgarwalSimrandeep KaurSulagna BhattacharyaSankar BhattacharyyaJosef T PrchalPrasenjit GuchhaitElsevierarticleαKGPHD2AktthrombosisinflammationSARS-CoV-2MedicineRMedicine (General)R5-920ENEBioMedicine, Vol 73, Iss , Pp 103672- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	αKG PHD2 Akt thrombosis inflammation SARS-CoV-2 Medicine R Medicine (General) R5-920
spellingShingle	αKG PHD2 Akt thrombosis inflammation SARS-CoV-2 Medicine R Medicine (General) R5-920 Nishith M Shrimali Sakshi Agarwal Simrandeep Kaur Sulagna Bhattacharya Sankar Bhattacharyya Josef T Prchal Prasenjit Guchhait α-Ketoglutarate Inhibits Thrombosis and Inflammation by Prolyl Hydroxylase-2 Mediated Inactivation of Phospho-Akt
description	Background: Phospho-Akt1 (pAkt1) undergoes prolyl hydroxylation at Pro125 and Pro313 by the prolyl hydroxylase-2 (PHD2) in a reaction decarboxylating α-ketoglutarate (αKG). We investigated whether the αKG supplementation could inhibit Akt-mediated activation of platelets and monocytes, in vitro as well as in vivo, by augmenting PHD2 activity. Methods: We treated platelets or monocytes isolated from healthy individuals with αKG in presence of agonists in vitro and assessed the signalling molecules including pAkt1. We supplemented mice with dietary αKG and estimated the functional responses of platelets and monocytes ex vivo. Further, we investigated the impact of dietary αKG on inflammation and thrombosis in lungs of mice either treated with thrombosis-inducing agent carrageenan or infected with SARS-CoV-2. Findings: Octyl αKG supplementation to platelets promoted PHD2 activity through elevated intracellular αKG to succinate ratio, and reduced aggregation in vitro by suppressing pAkt1(Thr308). Augmented PHD2 activity was confirmed by increased hydroxylated-proline and enhanced binding of PHD2 to pAkt in αKG-treated platelets. Contrastingly, inhibitors of PHD2 significantly increased pAkt1 in platelets. Octyl-αKG followed similar mechanism in monocytes to inhibit cytokine secretion in vitro. Our data also describe a suppressed pAkt1 and reduced activation of platelets and leukocytes ex vivo from mice supplemented with dietary αKG, unaccompanied by alteration in their number. Dietary αKG significantly reduced clot formation and leukocyte accumulation in various organs including lungs of mice treated with thrombosis-inducing agent carrageenan. Importantly, in SARS-CoV-2 infected hamsters, we observed a significant rescue effect of dietary αKG on inflamed lungs with significantly reduced leukocyte accumulation, clot formation and viral load alongside down-modulation of pAkt in the lung of the infected animals. Interpretation: Our study suggests that dietary αKG supplementation prevents Akt-driven maladies such as thrombosis and inflammation and rescues pathology of COVID19-infected lungs. Funding: Study was funded by the Department of Biotechnology (DBT), Govt. of India (grants: BT/PR22881 and BT/PR22985); and the Science and Engineering Research Board, Govt. of India (CRG/000092).
format	article
author	Nishith M Shrimali Sakshi Agarwal Simrandeep Kaur Sulagna Bhattacharya Sankar Bhattacharyya Josef T Prchal Prasenjit Guchhait
author_facet	Nishith M Shrimali Sakshi Agarwal Simrandeep Kaur Sulagna Bhattacharya Sankar Bhattacharyya Josef T Prchal Prasenjit Guchhait
author_sort	Nishith M Shrimali
title	α-Ketoglutarate Inhibits Thrombosis and Inflammation by Prolyl Hydroxylase-2 Mediated Inactivation of Phospho-Akt
title_short	α-Ketoglutarate Inhibits Thrombosis and Inflammation by Prolyl Hydroxylase-2 Mediated Inactivation of Phospho-Akt
title_full	α-Ketoglutarate Inhibits Thrombosis and Inflammation by Prolyl Hydroxylase-2 Mediated Inactivation of Phospho-Akt
title_fullStr	α-Ketoglutarate Inhibits Thrombosis and Inflammation by Prolyl Hydroxylase-2 Mediated Inactivation of Phospho-Akt
title_full_unstemmed	α-Ketoglutarate Inhibits Thrombosis and Inflammation by Prolyl Hydroxylase-2 Mediated Inactivation of Phospho-Akt
title_sort	α-ketoglutarate inhibits thrombosis and inflammation by prolyl hydroxylase-2 mediated inactivation of phospho-akt
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/1f095c1e831047149bf72cc927d00585
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α-Ketoglutarate Inhibits Thrombosis and Inflammation by Prolyl Hydroxylase-2 Mediated Inactivation of Phospho-Akt

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